The purpose ot this proposal is to examine the factors which regulate ureagenesis in the normal state, liver disease, and in traumatized or septic patients. The rapid activation of ureagenesis via N-acetylglutamate which we have observed in intact rats will be reinvestigated in (1) hepatocytes exposed to amino acids, lysed with digitonin and rapidly centrifuged to examine mitochondrial composition, and (2) in intact cats. In the latter, short-term changes in ureagenesis will be measured simultaneously following 13-C urea injection and will be correlated with liver composition measured sequentially. The same 13-C urea method will be applied to normal subjects infused with (1) glucose and (2) complete amino acid mixtures, to delineate the relationship between the rate of ureagenesis and plasma amino acid and ammonia concentrations. Hormones which modify these relationships will be examined, initially in rats and cats (as above), including somatostatin, glucagon, insulin, and adrenergic hormones and blockers. Low dose ethanol, sorbitol, and glycerol will be examined to determine whether they stimulate ureagenesis secondary to alterations of mitochondrial glutamate. Selected agents from these two groups will then be examined in normal man as above. Patients with cirrhosis, alcoholic hepatitis, and sepsis or trauma will be studied as above to determine whether ureagenesis as a function of amino acid concentration is abnormal. Depending upon the results of these experiments, protocols will be designed to attempt to correct these abnormalities in patients.